The beta6 (Glu toVal) mutation in the beta globin gene that leads to sickle cell anemia (SCA) has been known for many years, and the biophysical characteristics of intracellular sickling are well described, but the clinical heterogeneity in patients with SCA is poorly understood. Patients with SCA have a wide variability of clinical disease expression that is puzzling, despite efforts to identify globin gene modifiers such as alpha thalassemia, beta globin haplotype, or enhanced gamma globin expression. Our preliminary data suggest that genetic modifiers outside the globin gene loci can alter clinical disease expression in SCA, and we hypothesize that these genetic modifiers can predict the development of cerebrovascular and hepatobiliary disease in children with SCA. To test our hypothesis, we will analyze DNA samples from over 400 pediatric patients enrolled in two completed NHLBI-sponsored multicenter trials: (1) the Cooperative Study of Sickle Cell Disease (CSSCD) and (2) the Study to Prevent Stroke (STOP). We also include the upcoming Phase III infant hydroxyurea trial (BABY-HUG) that will add 200 additional DNA samples and the opportunity for direct patient contact and clinical research experience by trainees. We will test DNA samples from these unique pediatric cohorts for genetic polymorphisms (DNA mutations) in genes that collectively are important in thrombosis (e.g. methylenetetrahydrofolate reductase, platelet glycoprotein IIIa, plasminogen activator inhibitor, prothrombin, Factor V, and Factor VII genes), brain injury repair (apolipoprotein E), bilirubin metabolism (the UDP-glucuronosyltransferase), and iron accumulation (hereditary hemochromatosis gene). After determining the prevalence of each DNA mutation, we will correlate specific polymorphisms with patient data including laboratory measurements, clinical events, and radiological studies. The long-term goal is to identify genetic risk factors that influence the development of cerebrovascular and hepatobiliary disease, and to develop a prospective interventional clinical trial for children with SCA. Trainees will study laboratory techniques, statistical analysis, IRB protocol design, informed consent, ethical issues related to participation in clinical trials, and have direct patient contact with families participating in BABY-HUG.